C-Cluster enteroviruses are a group of highly infectious igents within Picornav7 dae, genus Enterovirus, that are characterized by closely related genotypes but vastly different pathogenic properties (poliomyelitis vs. respiratory disease). They can be sub-divided into three poliovirus (PV) and 11 C-cluster coxsackie A virus (C-CAy) species that differ principally in their use of the cellular receptor (hPVR and ICAM-1, respectively). The clustering of these viruses is based on very limited knowledge regarding genotypes. The structure at the atomic level of C-CAV virions is unknown making it impossible to relate surface function to structure and, thus, to the evolution of virion/receptor interaction. We propose to analyze the relationship between C-cluster enteroviruses, aiming at elucidating the evolutionary pathway by which these viruses chose to become coxsackie or polioviruses. This will include the determination of genotypes and molecular biology of several C-CAVs, the elucidation of the crystal structure of a C-CAy virion and its antigenic properties, and the analysis of receptor/virion interaction. The relationship between poliovirus and its human host has dramatically changed during the twentieth century. New measures of hygiene practiced for the first time in industrialized countries at the beginning of last century led, paradoxically, to devastating poliomyelitis epidemics that, in turn, prompted the development of effective vaccines. Indeed, efforts are underway to eradicate poliovirus globally. We have entertained the possibility that in a world free of poliovirus and anti-polio antibodies some C-CA Vs may switch receptors (ICAM-l to CD155) to evolve as novel polioviruses. To assess this scenario we propose to establish a model system to test possibilities of speciation of C-cluster enteroviruses.